Biologic systems and complex chemical processes, such as biochemical pathways, cellular activities, synthetic organic processes, and molecular interactions (collectively referred to bio/chemical activity herein) pose considerable challenges to scientists interested in directly monitoring activities. Such systems usually are rather complex, existing in environments where a number of differing activities are occurring simultaneously, and are thus noisy. Currently, there are a number of general techniques routinely used for detecting biochemical phenomena [David Freifelder, Physical Biochemistry, 1982, second edition, W. H. Freeman & Co., New York], most of which employ techniques in which one or more of the constituents of the system is labeled in some fashion; often times, these labeling approaches show whether or not a particular event has occurred, such as the binding of one molecule to another, or altered activity of a particular step in a biochemical pathway [D. E. Koshland, 1970, The Molecular Basis for Enzyme Regulation, in The Enzymes, P. Boyer, Ed., 341-396, Academic Press]. A very limited number of techniques utilize the measurement of properties which directly measure some physiologic property of a system, or do not require the attachment of a label. However, in these cases, only a very limited amount of information is available, and in most cases, the techniques are difficult to carry out, and thus the throughput is extremely limited.
Many chemical and biological systems are amenable to direct physiologic detection, such as through the use electronic measurement techniques. Many activities of interest in these areas result in direct or indirect changes in the electromagnetic properties of the system. Indeed, numerous methods have been developed in which various electronic and electromagnetic properties of the system are monitored, and changes therein are correlated to the presence or absence of one or more activities. Electronic and electromagnetic monitoring has many advantages over other methods of detection: Electronic systems can be made very small, can be scaled to very high densities and/or large parallel systems, can be manufactured very cheaply, and are highly durable and impervious to environmental factors.
In order for a given system to be amenable to electronic and electromagnetic monitoring, as is currently practiced in the art, the system, and changes therein, must produce a large enough signal to be measured. To be more precise, the signal needs to be detectable over the background noise which is almost always present in such systems. This poses many problems for the general application of these techniques to chemical and biologic systems, as there often is a high level of inherent noise, and small changes due do specific chemical or biologic activities are therefore not detectable. For example, many systems are comprised largely of water and ionic species, both of which exhibit large changes in their electrical properties as a function of temperature. Small changes in ambient temperature produce changes in the electrical properties of the system being studied, thus rendering the signal effectively undetectable. Another relevant example is the detection of s specific activity in a complex mixture, such as a suspension of biologic cells or tissues; there are multiple activities on-going at any given time, so the detection of a specific activity is very challenging, at least if its signal is not easily separated from all of the other signals in the system.
The have been many attempts to address the problem of specificity and noise in electronic detection modalities. In many cases, the signal measured electromagnetically is derivative of the activity desired to be monitored. In most of these cases, the specific activity or activities it is desired to detect is directly or indirectly coupled to a system which effectively amplifies the signal, and thus makes it detectable. Examples of this include enzymatic processes, in which a particular analyte is modified in some way that renders it more easily detected. One such example is the use of the enzyme glucose oxidase to change an uncharged species (glucose) into charged species (gluconic acid), resulting in a change in the conductance of the medium in which the glucose resides. The change in conductance can then be detected using conventional instruments for the measurement of electrical conductivity. Other approaches involve altering the oxidation-reduction characteristics of a given analyte, creating dense monolayers of specific chemistries on conductive surfaces, in order to alter the contact resistance and/or reactance as a marker for activity. Yet another class of approaches is the creation of ultra-sensitive measurement modalities, for the purpose of directly measuring altered electrical and/or dielectric properties which result from some specific activity in the system.
Each of the above-mentioned approaches has limitations. In systems where some form of amplification needs to take place, the added burden of incorporating a mechanism for amplification is time consuming, incurs costs, and in many cases is not possible. In cases where ultra-sensitive measurement systems are used, there are often considerable costs, and often the size and throughput of the system makes it unsuitable for many applications.
Thus, although electronic detection has found utility in biological, chemical, medical, and industrial applications, there exist significant limitations which prevent larger utility. Accordingly, there is need for a system operable to measure, monitor and detect biologic and chemical activities using electronic and electromagnetic measurement modalities.